Prasugrel, also known as 2-[2-(acetyloxy)-6,7-dihydrothieno[3,2-c]-pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone, is a thienopyridine drug developed by Sankyo (Daiichi Sankyo) and Eli Lilly, and approved by EU on 23 Feb. 2009 as a platelet aggregation inhibitor. Prasugrel has Formula (I) as shown below:

Prasugrel and pharmaceutical acceptable salts thereof are platelet aggregation inhibitors from the thienopyridine class of ADP (Adenosine diphosphate) receptor for prophylaxis and therapy of thrombosis with improved oral bioavailability and rapid onset. However, highly pure prasugrel and pharmaceutical salts thereof needed to be provided when used as a medicine.
There are many methods for preparing prasugrel. A common method used to prepare prasugrel is by condensing halogen substituted cyclopropyl-2-fluorobenzyl ketone with 5,6,7,7a-tetrahydrothieno[3,2-c]pyridine-2(4H)-one to obtain a condensation product. The condensation product is then mixed with an acetylation agent in toluene, DMF, etc. to produce prasugrel (I). The above method is described in PCT publication WO 96/11203 as shown in the following scheme:
wherein R in Formula (III) and (V) is a hydroxy protecting group.
However, there are some disadvantages in the aforementioned preparation methods, such as the acetylation reaction is carried out in toxic or high boiling solvents, such as acetonitrile, dimethylformamide or toluene, which are harmful to environment as well as health. Furthermore, removing high boiling solvents such as dimethylformamide or toluene requires a high temperature. However, the prasugrel free base and its intermediate thereof are thermally instable, and prone to degradation at the high temperature. Therefore, the purity of the final product is low, which makes it unsuitable for use as an active pharmaceutical ingredient (API). Moreover, recycling the high boiling solvents is energy consuming and thus costly.
PCT Patent Publication No. WO 96/11203, Japanese Patent Publication No. 2002/145883 and U.S. Pat. No. 6,693,115 describe a method for preparing prasugrel hydrochloride having formula (II) by mixing hydrochloric acid with prasugrel free base of Formula (I):

However, prasugrel hydrochloride prepared by the aforementioned method exists in mixture of unknown polymorphic forms, which may have significant differences from each other in appearances, solubilities, melting points, dissolution rates, bioavailabilities, stability, efficacy and the like. Therefore, there is a need for considering the issue of polymorph in developing a pharmaceutical product.
So far, it is known that prasugrel hydrochloride exists in several polymorphic forms. Crystalline forms A, B1 and B2 of prasugrel hydrochloride was first disclosed in PCT Patent Publication No. WO 2002/004461. PCT Patent Publication No. WO 2009/062044 has disclosed crystalline forms C, D and E as well as amorphous prasugrel hydrochloride. PCT Patent Publication No. WO 2010/070677 has disclosed crystalline forms G1 and G2.